General Information

Clolar (clofarabine) is an anti-neoplastic purine nucleoside
analog used to treat lymphoblastic leukemia . The drug acts as an
anti-metabolite, interfering with DNA replication. In addition, the
drug appears to disrupt the integrity of the mitochondrial
membrane, releasing pro-apoptotic mitochondrial proteins,
cytochrome C and apoptosis-inducing factor, activating pathways of
programmed cell death. In these ways Clolar exerts a cytotoxic
effect on both rapidly dividing and quiescent cancer cells.

Clolar is administered as an intravenously, with a recommended
dosage of 52 mg/m2 via 2-hour infusion dialy for 5 days, with cycle
repeats every 2-6 weeks once organ function has returned to
baseline.

Clinical Results

FDA approval of Clolar was based on a pair of clinical trials,
involving a total of 66 pediatric ALL patients. The first was a
open-label, dose-escalation, noncomparative study, which enrolled a
total of 17 pediatric ALL patients . Subjects received escalating
doses of the drug ranging from 11.25 mg/m2 to 70 mg/m2, daily for 5
days. 9 of the 17 received the recommended dose of 52 mg/m2. Among
all patients 2 complete and 2 patial responses were observed. Dose
limiting toxicities, including reversible hyperbilirubinemia and
elevated transaminase levels and skin rash, were observed at 70
mg/m2, leading to the choice of 52 mg/m2 as the optimum dose.

The second study was a single arm, open label study which
enrolled 49 pediatric ALL patients. Subjects in this study received
up to sequential cycles at the recommended dose (52 mg/m2 x 5
days), with no dose escalation. Efficacy was observed in the
trial's primary endpoint, the overall rate of response.
Specifically, there were 6 completer responses (CR; 12.2%), 4
complete responses which did not also demonstrate platelet recovery
(CRp; 8.2%), and 5 partial responses (PR; 10.2%), for a total
response rate of 30.6%. Among the 9 responding patients who did not
undergo bone marrow transplant following treatment, response
durations were as follows: 43, 50, 82, 93+ and 160+ days for CR
subjects, 32 days for one CRp subject, and 7, 16, and 21 days for
PR subjects.

Side Effects

Adverse events associated with the use of Clolar may include
(but are not limited to) the following:

Febrile neutropenia

Systemic Inflammatory Response Syndrome (SIRS)

Vomiting

Nausea

Diarrhea

Pyrexia

Rigors

Abdominal Pain

Fatigue

Tachycardia

Anorexia Additionally, animal models have demostrated
teratogenic potential in pregnant women. Human embryo toxicity has
not been investigated, but the likelyhood of risk to the fetus is
very high, and pregnancy should be avoided while receiving
Clolar.

Mechanism of Action

Clolar disrupts DNA synthesis and causes fatal replication
errors through the disruption of several intracellular syntetic
pathways. Specifically, the drug depletes deoxynucleotide
triphosphate pools through the inhibition of ribonucleotide
reductase, and causes termination of DNA chain elongation through
incorporation into the DNA strand and competitive inhibition of DNA
polymerases. Furthermore, the drug has been shown to disrupt
mitochondrial membrane intergrity, possibly through disruption of
mitochondrial DNA synthesis. Disruption of mitochondrial integrity
leads to the release of the pro-apoptotic mitochondrial proteins,
cytochrome C and apoptosis-inducing factor, which activate
programmed cell death pathways.